Publications by authors named "Miryam Carecchio"

56 Publications

Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series.

Neurogenetics 2021 Jan 20. Epub 2021 Jan 20.

Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.

Primary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-021-00634-9DOI Listing
January 2021

EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.

Ann Neurol 2021 Mar 15;89(3):485-497. Epub 2020 Dec 15.

Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia.

Methods: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients.

Results: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia.

Interpretation: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25973DOI Listing
March 2021

Harmful Iron-Calcium Relationship in Pantothenate kinase Associated Neurodegeneration.

Int J Mol Sci 2020 May 22;21(10). Epub 2020 May 22.

IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.

Pantothenate Kinase-associated Neurodegeneration (PKAN) belongs to a wide spectrum of diseases characterized by brain iron accumulation and extrapyramidal motor signs. PKAN is caused by mutations in PANK2, encoding the mitochondrial pantothenate kinase 2, which is the first enzyme of the biosynthesis of Coenzyme A. We established and characterized glutamatergic neurons starting from previously developed PKAN Induced Pluripotent Stem Cells (iPSCs). Results obtained by inductively coupled plasma mass spectrometry indicated a higher amount of total cellular iron in PKAN glutamatergic neurons with respect to controls. PKAN glutamatergic neurons, analyzed by electron microscopy, exhibited electron dense aggregates in mitochondria that were identified as granules containing calcium phosphate. Calcium homeostasis resulted compromised in neurons, as verified by monitoring the activity of calcium-dependent enzyme calpain1, calcium imaging and voltage dependent calcium currents. Notably, the presence of calcification in the internal was confirmed in seven out of 15 genetically defined PKAN patients for whom brain CT scan was available. Moreover, we observed a higher prevalence of brain calcification in females. Our data prove that high amount of iron coexists with an impairment of cytosolic calcium in PKAN glutamatergic neurons, indicating both, iron and calcium dys-homeostasis, as actors in pathogenesis of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21103664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279353PMC
May 2020

-related disease is associated with central pontine calcifications and atypical parkinsonism.

Neurol Genet 2020 Apr 20;6(2):e399. Epub 2020 Feb 20.

Department of Neuromuscular Diseases (V.C., S.E., L.S., J.V., V.S., N.W.W., H.H.), UCL Queen Square Institute of Neurology; National Hospital for Neurology and Neurosurgery (V.C., S.E., L.S., J.V., V.S., N.W.W., H.H.), Queen Square, London, UK; Department of Neurology and Neurosurgery (V.C., S.G.), Institute of Emergency Medicine, Chisinau, Republic of Moldova; Department of Neuroscience (M.C.), University of Padua, Italy; Northern Ireland Regional Genetics Service (G.R., P.J.M.), Belfast City Hospital, UK; Department of Neuroscience (A.B.), Interdisciplinary Center (IDC) Herzliya, Israel; Department of Paediatrics & Child Health (S.K., F.J., S.I., F.K., Z.Q.), Aga Khan University, Karachi, Pakistan; Department of Neurology (L.M.), Eastern Piedmont University, Novara, Italy; Department of Neurology (E.S., D.P.) and Department of Neuroradiology (L.C.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Department of Clinical Neurology (N.B.), University of Nottingham, UK; Department of Clinical and Movement Neurosciences (B.B., K.P.B., N.W.W.), UCL Queen Square Institute of Neurology, London, UK; Department of Neurology (B.B.), Heidelberg University Hospital, Germany; Reta Lila Weston Institute (A.L.), UCL Queen Square Institute of Neurology, London, UK; and Medical Genetics and Neurogenetics Unit (B.G.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Objective: To identify the phenotypic, neuroimaging, and genotype-phenotype expression of mutations.

Methods: Using next-generation sequencing, we screened 86 patients with primary familial brain calcification (PFBC) from 60 families with autosomal recessive or absent family history that were negative for mutations in , , , and . In-depth phenotyping and neuroimaging investigations were performed in all cases reported here.

Results: We identified 12 distinct deleterious variants in 7 of the 60 families with PFBC. Overall, biallelic mutations accounted for 11.6% of PFBC families in our cohort. A heterogeneous phenotypic expression was identified within and between families with a median age at onset of 56.4 years, a variable combination of parkinsonism, cerebellar signs, and cognitive decline. Psychiatric disturbances were not a prominent feature. Cognitive assessment showed impaired cognitive function in 62.5% of cases. Parkinsonism associated with vertical nuclear gaze palsy was the initial clinical presentation in 1/3 of cases and was associated with central pontine calcifications. Cerebral cortical atrophy was present in 37% of cases.

Conclusions: This large, multicentric study shows that biallelic mutations represent a significant proportion of autosomal recessive PFBC. We recommend screening mutations in all patients with primary brain calcifications and autosomal recessive or negative family history, especially when presenting clinically as atypical parkinsonism and with pontine calcification on brain CT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073457PMC
April 2020

Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 Novel Variants.

J Clin Med 2020 Mar 3;9(3). Epub 2020 Mar 3.

Regional Coordinator Centre for Rare Diseases, University Hospital of Udine, 33100 Udine, Italy.

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in or genes. In 2009, the molecular characterization of 44 NPC Italian patients has been published. Here, we present an update of the genetic findings in 105 Italian NPC patients belonging to 83 unrelated families (77 NPC1 and 6 NPC2). and genes were studied following an algorithm recently published. Eighty-four different and five alleles were identified. Only two alleles remained non detected. Sixty-two percent of alleles were due to missense variants. The most frequent mutation was the p.F284Lfs*26 (5.8% of the alleles). All mutations were found in the homozygous state, and all but one was severe. Among newly diagnosed patients, 18 novel mutations were identified. The pathogenic nature of 7/9 missense alleles and 3/4 intronic variants was confirmed by filipin staining and NPC1 protein analysis or mRNA expression in patient's fibroblasts. Taken together, our previous published data and new results provide an overall picture of the molecular characteristics of NPC patients diagnosed so far in Italy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9030679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141276PMC
March 2020

Pallidal Deep Brain Stimulation in DYT6 Dystonia: Clinical Outcome and Predictive Factors for Motor Improvement.

J Clin Med 2019 Dec 6;8(12). Epub 2019 Dec 6.

Department of Women's and Children's Health, Karolinska Institutet, 17176 Stockholm, Sweden.

Pallidal deep brain stimulation is an established treatment in dystonia. Available data on the effect in DYT-THAP1 dystonia (also known as DYT6 dystonia) are scarce and long-term follow-up studies are lacking. In this retrospective, multicenter follow-up case series of medical records of such patients, the clinical outcome of pallidal deep brain stimulation in DYT-THAP1 dystonia, was evaluated. The Burke Fahn Marsden Dystonia Rating Scale served as an outcome measure. Nine females and 5 males were enrolled, with a median follow-up of 4 years and 10 months after implant. All benefited from surgery: dystonia severity was reduced by a median of 58% (IQR 31-62, = 0.001) at last follow-up, as assessed by the Burke Fahn Marsden movement subscale. In the majority of individuals, there was no improvement of speech or swallowing, and overall, the effect was greater in the trunk and limbs as compared to the cranio-cervical and orolaryngeal regions. No correlation was found between disease duration before surgery, age at surgery, or preoperative disease burden and the outcome of deep brain stimulation. Device- and therapy-related side-effects were few. Accordingly, pallidal deep brain stimulation should be considered in clinically impairing and pharmaco-resistant DYT-THAP1 dystonia. The method is safe and effective, both short- and long-term.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8122163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947218PMC
December 2019

Parkinsonism in neurometabolic diseases.

Authors:
Miryam Carecchio

Int Rev Neurobiol 2019 21;149:355-376. Epub 2019 Nov 21.

Department of Neuroscience, University of Padua, Padua, Italy.

Neurometabolic disease are a wide and variegate group of genetic disorders, mostly recessively inherited, causing an alteration of specific biochemical pathways within cells. In most cases, they are characterized by a multi-organ involvement, but some diseases specifically affect the brain resulting in progressive neurodegenerative conditions. Though rare or ultra-rare, these disorders must be considered in the differential of adult-onset parkinsonism in the presence of atypical additional elements, such as hepatic dysfunction, bone alterations, hematological abnormalities, rapid motor deterioration or disease-specific clinical signs. Among these rare diseases, some are treatable, including some metal-accumulation disorders and some lysosomal storage diseases. Current available therapies, including chelating agents for metals and Enzyme Replacement Therapies can dramatically improve the natural history of some neurometabolic diseases, either by slowing disease progression or by reverting clinical signs and symptoms. Hence, it essential to recognize the most frequent neurometabolic disorders to achieve a timely diagnosis and start appropriate therapeutical interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.irn.2019.10.009DOI Listing
June 2020

Adult diagnosis of Cockayne syndrome.

Neurology 2019 11;93(19):854-855

From the Department of Neurology (A.C., D.C., A.A.), IRCCS Humanitas Research Hospital and University, Rozzano, Milan; Department of Neuroscience (M.C.), University of Padua; Medical Genetics and Neurogenetics Unit (B.G.), IRCCS Carlo Besta Neurological Institute; and Department of Neurology (A.A.), Catholic University, Milan, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008449DOI Listing
November 2019

Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study.

Mov Disord 2019 10 19;34(10):1516-1527. Epub 2019 Jun 19.

Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background: Childhood-onset dystonia is often genetically determined. Recently, KMT2B variants have been recognized as an important cause of childhood-onset dystonia.

Objective: To define the frequency of KMT2B mutations in a cohort of dystonic patients aged <18 years at onset, the associated clinical and radiological phenotype, and the natural history of disease.

Methods: Whole-exome sequencing or customized gene panels were used to screen a cohort of 65 patients who had previously tested negative for all other known dystonia-associated genes.

Results: We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was classified as a variant of unknown significance. We also identified 2 additional patients carrying pathogenic mutations in GNAO1 and ATM. Overall, we established a definitive genetic diagnosis in 23% of cases. We observed a spectrum of clinical manifestations in KMT2B variant carriers, ranging from generalized dystonia to short stature or intellectual disability alone, even within the same family. In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization. Eight patients underwent pallidal DBS with a median decrease of Burke-Fahn-Marsden Dystonia Rating Scale-Motor score of 38.5% in the long term. We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance.

Conclusions: KMT2B mutations are frequent in childhood-onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features. A dramatic and long-lasting response to DBS is characteristic of DYT-KMT2B dystonia. © 2019 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27771DOI Listing
October 2019

Spasmodic dysphonia as a presenting symptom of spinocerebellar ataxia type 12.

Neurogenetics 2019 08 13;20(3):161-164. Epub 2019 Jun 13.

Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Autosomal dominant spinocerebellar ataxia (SCA) type 12 is a rare SCA characterized by a heterogeneous phenotype. Action tremor of the upper limbs is the most common presenting sign and cerebellar signs can appear subsequently. In many cases, minor signs, like dystonia, can be predominant even at onset. Laryngeal dystonia (spasmodic dysphonia) has been observed only in one case of SCA12 and never reported at disease onset. We present a 61-year-old female who developed spasmodic dysphonia followed by dystonic tremor and subsequent ataxia diagnosed with SCA12. Thus, spasmodic dysphonia can be a presenting symptom of SCA12.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-019-00580-7DOI Listing
August 2019

Long-term effect of subthalamic and pallidal deep brain stimulation for status dystonicus in children with methylmalonic acidemia and GNAO1 mutation.

J Neural Transm (Vienna) 2019 06 10;126(6):739-757. Epub 2019 May 10.

Department of Neurosciences, University of Padova, Padua, Italy.

Status dystonicus (SD) is a rare and potentially life-threatening condition requiring intensive care management. Deep brain stimulation (DBS) has emerged as an effective treatment for SD refractory to medical management, but its application in this field is still limited. Here, we report the long-term outcome of four pediatric patients treated with DBS at the University Hospital of Padua, Italy, for SD refractory to medications. In addition, we present the results of a systematic literature review aimed at identifying published cases of SD treated with DBS, with focus on motor outcome. In our cohort, two children were affected by methylmalonic acidemia and suffered acute basal ganglia lesions, while the other two carried a pathogenic mutation in GNAO1 gene. DBS target was subthalamic nucleus (STN) in one case and globus pallidus internus (GPi) in three. All patients experienced SD resolution within 8-19 days after surgery. Mean post-operative follow-up was 5 years. We identified in the literature 53 additional SD cases treated with DBS (median age at DBS implantation: 12 years) with reported positive outcome in 51 and resolution of SD in a mean of 17 days after surgery. Our findings indicate that DBS is an effective treatment for SD refractory to medications, even in patients with acute basal ganglia lesions; STN can be an appropriate target when GPi is damaged. Moreover, data from long-term follow-up show that SD recurrences can be significantly reduced in frequency or abolished after DBS implantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-019-02010-2DOI Listing
June 2019

Inborn errors of coenzyme A metabolism and neurodegeneration.

J Inherit Metab Dis 2019 01;42(1):49-56

Unit of Molecular Neurogenetics - Pierfranco and Luisa Mariani Centre for the Study of Mitochondrial Disorders in Children, Foundation IRCCS Neurological Institute C. Besta, Via Temolo 4, Milan 20126, Italy.

Two inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase-associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway. Another very rare but similar disorder, denominated CoPAN, is caused by mutations in coenzyme A synthase gene (COASY) coding for a bi-functional mitochondrial enzyme, which catalyzes the final steps of CoA biosynthesis. It still remains a mystery why dysfunctions in CoA synthesis lead to neurodegeneration and iron accumulation in specific brain regions, but it is now evident that CoA metabolism plays a crucial role in the normal functioning and metabolism of the nervous system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jimd.12026DOI Listing
January 2019

Encephalopathies with intracranial calcification in children: clinical and genetic characterization.

Orphanet J Rare Dis 2018 08 16;13(1):135. Epub 2018 Aug 16.

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.

Background: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses.

Methods: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification.

Results: We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two.

Conclusions: Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-018-0854-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6094574PMC
August 2018

Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Eur J Hum Genet 2018 10 28;26(10):1462-1477. Epub 2018 Jun 28.

Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-018-0185-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138755PMC
October 2018

Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.

Hum Mutat 2018 07 17;39(7):965-969. Epub 2018 May 17.

Department of Human Genetics, University of Michigan, Ann Arbor, Michigan.

Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter the biophysical properties of the channel. Complete loss-of-function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg, in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment. Functional analysis of the p.Pro1719Arg variant in transfected neuron-derived cells demonstrated greatly reduced Na 1.6 channel activity without altered gating properties. Hypomorphic alleles of Scn8a in the mouse are known to result in similar movement disorders. This study expands the phenotypic and functional spectrum of SCN8A variants to include inherited nonepileptic isolated myoclonus. SCN8A can be considered as a candidate gene for isolated movement disorders without seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032947PMC
July 2018

The Length of Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson's Disease.

Front Neurol 2018 29;9:213. Epub 2018 Mar 29.

Section of Neurology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Background: Alpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson's disease (PD). A previous study showed that a variant of the alpha-synuclein gene (), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients.

Methods: We recruited and genotyped for Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox's proportional hazards regression model.

Results: Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups.

Conclusion: Rep1 263 allele is associated with a worse cognitive outcome in PD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2018.00213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890103PMC
March 2018

Recessive mutations in VPS13D cause childhood onset movement disorders.

Ann Neurol 2018 06 10;83(6):1089-1095. Epub 2018 Apr 10.

Department of Pediatrics, Saint Justine University Hospital Center and University of Montreal, Montreal, Canada.

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25204DOI Listing
June 2018

CANS: Childhood acute neuropsychiatric syndromes.

Eur J Paediatr Neurol 2018 03;22(2):316-320

Fondazione IRCSS Istituto Neurologico Carlo Besta, Milan, Italy. Electronic address:

The terms Pediatric Autoimmune Neuropsychiatric disorders associated with streptococcal infections (PANDAS), Pediatric acute-onset neuropsychiatric Syndrome (PANS), and Childhood Acute Neuropsychiatric Symptoms (CANS) have been used to describe certain acute onset neuropsychiatric pediatric disorders. This clinical characteristic was unusually abrupt onset of obsessive compulsive symptoms and/or severe eating restrictions and concomitant cognitive, behavioral or neurological symptoms. Because the CANS/PANS criteria define a broad spectrum of neuropsychiatric conditions, the syndrome is presumed to result from a variety of disease mechanisms and to have multiple etiologies, ranging from postinfectious autoimmune and neuroinflammatory disorders to toxic, endocrine or metabolic disorders. We suggest a diagnostic flow-chart in case of acute onset neuropsychiatric syndrome to better define diagnostic criteria, identify possible subtypes and delineate treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2018.01.011DOI Listing
March 2018

The relevance of gene panels in movement disorders diagnosis: A lab perspective.

Eur J Paediatr Neurol 2018 Mar 31;22(2):285-291. Epub 2018 Jan 31.

Molecular Neurogenetics Unit, IRCCS Foundation Neurological Institute C. Besta, Via L. Temolo 4, 20126 Milan, Italy. Electronic address:

Next-Generation Sequencing (NGS) is a group of new methods that allow sequencing a variable number of known genes (targeted resequencing) or even the whole human genome (whole genome sequencing-WGS) and have contributed to an exponential genetic knowledge growth, especially in rare diseases, in the past few years. Since 2015, in the Molecular Neurogenetics Unit of Neurological Institute "Carlo Besta", some gene panels have become available to screen all the known genes associated with Movement Disorders (MD) in children and adults as a diagnostic package. Over 221 patients analyzed (part of the Telethon Network of Genetic Biobanks - TNGB), pathogenic variants were found in 25 (11.31%), allowing a definitive genetic diagnosis. Among them, we found mutations in 10/114 patients with dystonia (8.8%); 10/59 patients with Parkinson's disease (16.9%); 1/25 patients with Neurodegeneration with Brain Iron Accumulation (NBIA) (4%) and 4/23 patients with neurotransmitter and biopterin metabolism synthesis defect (17.4%). Our results are in line with those published in literature; targeted resequencing does not replace Sanger sequencing totally, but its usage needs to be discussed with clinicians taking into account both the patient's clinical picture and radiological and neurophysiological data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2018.01.013DOI Listing
March 2018

Diagnosis and treatment of pediatric onset isolated dystonia.

Eur J Paediatr Neurol 2018 Mar 17;22(2):238-244. Epub 2018 Jan 17.

Department of Paediatric Neurology, IRCCS Fondazione C. Besta, Milan, Italy.

Isolated dystonia refers to a genetic heterogeneous group of progressive conditions with onset of symptoms during childhood or adolescence, progressive course with frequent generalization and marked functional impairment. There are well-known monogenic forms of isolated dystonia with pediatric onset such as DYT1 and DYT6 transmitted with autosomal dominant inheritance and low penetrance. Genetic findings of the past years have widened the etiological spectrum and the phenotype. The recently discovered genes (GNAL, ANO-3, KTM2B) or variant of already known diseases, such as Ataxia-Teleangectasia, are emerging as another causes of pediatric onset dystonia, sometimes with a more complex phenotype, but their incidence is unknown and still a considerable number of cases remains genetically undetermined. Due to the severe disability of pediatric onset dystonia treatment remains unsatisfactory and still mainly based upon oral pharmacological agents. However, deep brain stimulation is now extensively applied with good to excellent results especially when patients are treated early during the course of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2018.01.006DOI Listing
March 2018

ATP1A3-related disorders: An update.

Eur J Paediatr Neurol 2018 Mar 21;22(2):257-263. Epub 2017 Dec 21.

Department of Pediatric Neurology, IRCCS Foundation Carlo Besta Neurological Institute, Via Celoria 11, 20131 Milan, Italy. Electronic address:

Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) are three distinct, yet partially overlapping clinical syndromes that have long been thought to be allelic disorders. From 2004 to 2012, both autosomal dominant and de novo mutations in ATP1A3 have been detected in patients affected by these three conditions. Growing evidence suggests that AHC, RDP and CAPOS syndrome are part of a large and continuously expanding clinical spectrum and share some recurrent clinical features, such as abrupt-onset, asymmetric anatomical distribution and the presence of triggering factors, which are highly suggestive of ATP1A3 mutations. In this review, we will highlight the main clinical and genetic features of ATP1A3-related disorders focussing on shared and distinct features that can be helpful in clinical practice to individuate mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2017.12.009DOI Listing
March 2018

SPG5 siblings with different phenotypes showing reduction of 27-hydroxycholesterol after simvastatin-ezetimibe treatment.

J Neurol Sci 2017 12 16;383:39-41. Epub 2017 Oct 16.

Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2017.10.022DOI Listing
December 2017

Emerging Monogenic Complex Hyperkinetic Disorders.

Curr Neurol Neurosci Rep 2017 Oct 30;17(12):97. Epub 2017 Oct 30.

Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA.

Purpose Of Review: Hyperkinetic movement disorders can manifest alone or as part of complex phenotypes. In the era of next-generation sequencing (NGS), the list of monogenic complex movement disorders is rapidly growing. This review will explore the main features of these newly identified conditions.

Recent Findings: Mutations in ADCY5 and PDE10A have been identified as important causes of childhood-onset dyskinesias and KMT2B mutations as one of the most frequent causes of complex dystonia in children. The delineation of the phenotypic spectrum associated with mutations in ATP1A3, FOXG1, GNAO1, GRIN1, FRRS1L, and TBC1D24 is revealing an expanding genetic overlap between epileptic encephalopathies, developmental delay/intellectual disability, and hyperkinetic movement disorders,. Thanks to NGS, the etiology of several complex hyperkinetic movement disorders has been elucidated. Importantly, NGS is changing the way clinicians diagnose these complex conditions. Shared molecular pathways, involved in early stages of brain development and normal synaptic transmission, underlie basal ganglia dysfunction, epilepsy, and other neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11910-017-0806-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662693PMC
October 2017

A PDE10A de novo mutation causes childhood-onset chorea with diurnal fluctuations.

Mov Disord 2017 11 26;32(11):1646-1647. Epub 2017 Sep 26.

Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.27175DOI Listing
November 2017

Patient Affected by Beta-Propeller Protein-Associated Neurodegeneration: A Therapeutic Attempt with Iron Chelation Therapy.

Front Neurol 2017 21;8:385. Epub 2017 Aug 21.

Department of Biomedical and Specialistic Surgical Sciences, Section of Neurological, Psychiatric and Psychological Sciences, Ferrara University, Ferrara, Italy.

Here, we report the case of a 36-year-old patient with a diagnosis of mutation of the WDR45 gene, responsible for beta-propeller protein-associated neurodegeneration, a phenotypically distinct, X-linked dominant form of Neurodegeneration with Brain Iron Accumulation. The clinical history is characterized by a relatively stable intellectual disability and a hypo-bradykinetic and hypertonic syndrome with juvenile onset. Genetic investigations and T1 and T2-weighted MR images align with what is described in literature. The patient was also subjected to PET with 18-FDG investigation and DaT-Scan study. In reporting relevant clinical data, we want to emphasize the fact that the patient received a chelation therapy with deferiprone (treatment already used in other forms of NBIA with encouraging results), which, however, had to be interrupted because the parkinsonian symptoms worsened. Conversely, the patient has benefited from non-drug therapies and, in particular, from an adapted motor activity with assisted pedaling (method in the process of validation in treatments of parkinsonian syndromes), which started before the treatment with deferiprone and still continues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2017.00385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573443PMC
August 2017

Rare causes of early-onset dystonia-parkinsonism with cognitive impairment: a de novo PSEN-1 mutation.

Neurogenetics 2017 Jul 29;18(3):175-178. Epub 2017 Jun 29.

Molecular Neurogenetics Unit, IRCCS Foundation C. Besta Neurological Institute, Via L. Temolo n. 4, 20126, Milan, Italy.

Mutations in PSEN1 are responsible for familial Alzheimer's disease (FAD) inherited as autosomal dominant trait, but also de novo mutations have been rarely reported in sporadic early-onset dementia cases. Parkinsonism in FAD has been mainly described in advanced disease stages. We characterized a patient presenting with early-onset dystonia-parkinsonism later complicated by dementia and myoclonus. Brain MRI showed signs of iron accumulation in the basal ganglia mimicking neurodegeneration with brain iron accumulation (NBIA) as well as fronto-temporal atrophy. Whole exome sequencing revealed a novel PSEN1 mutation and segregation within the family demonstrated the mutation arose de novo.We suggest considering PSEN1 mutations in cases of dystonia-parkinsonism with positive DAT-Scan, later complicated by progressive cognitive decline and cortical myoclonus even without a dominant family history.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-017-0518-4DOI Listing
July 2017

Parkinson disease in Gaucher disease.

J Clin Mov Disord 2017 23;4. Epub 2017 May 23.

Molecular Neurogenetics Unit, IRCCS Foundation Carlo Besta Neurological Institute, Milan, Italy.

Background: Gaucher disease (GD) is an inborn error of metabolism caused by mutations in the gene () coding for glucocerebrosidase (GCase), inherited in an autosomal recessive pattern. GD patients have up to 9% risk of developing PD.

Case Presentation: We report two patients with GD that developed PD at different disease stages.

Conclusion: We reviewed the literature on the coexistence of PD and GD and speculate that the severity of symptoms may be related to the type of GBA mutation inherited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40734-017-0054-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440911PMC
May 2017

ADCY5-related movement disorders: Frequency, disease course and phenotypic variability in a cohort of paediatric patients.

Parkinsonism Relat Disord 2017 Aug 10;41:37-43. Epub 2017 May 10.

Department of Pediatric Neurology, IRCCS Foundation Neurological Institute C. Besta, Via Celoria 11, 20133 Milan, Italy.

Introduction: ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated.

Methods: We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders.

Results: We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence.

Conclusion: Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2017.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549507PMC
August 2017

DYT2 screening in early-onset isolated dystonia.

Eur J Paediatr Neurol 2017 Mar 13;21(2):269-271. Epub 2016 Oct 13.

Molecular Neurogenetics Unit, IRCCS Foundation C. Besta Neurological Institute, Milan, Italy. Electronic address:

Background: Mutations in HPCA, a gene implicated in calcium signaling in the striatum, have been recently described in recessive dystonia cases previously grouped under the term "DYT2 dystonia". Positive patients reported so far show focal onset during childhood with subsequent generalization and a slowly progressive course to adulthood.

Methods: 73 patients with isolated dystonia of various distribution, manifesting within 21 years of age, were enrolled in this Italian study and underwent a mutational screening of HPCA gene by means of Sanger sequencing.

Results/conclusions: Mean age at onset was 10.2 (±5.1) years and mean age at the time of genetic testing was 33 (±14.2) years. Mean disease duration at the time of enrollment was 22.7 (±12.8) years. None of the patients enrolled was found to carry HPCA mutations, rising suspicion that these probably represent a very rare cause of dystonia in childhood-adolescence. Larger studies will help determining the real mutational frequency of this gene also in different ethnic groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2016.10.001DOI Listing
March 2017

Growth Arrest Specific 6 Concentration is Increased in the Cerebrospinal Fluid of Patients with Alzheimer's Disease.

J Alzheimers Dis 2017 ;55(1):59-65

Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Piemonte Orientale, Novara, Italy.

Growth arrest specific 6 (Gas6) has neurotrophic and neuroinflammatory functions, and may play a role in Alzheimer's disease (AD). In keeping with this hypothesis, we observed that cerebrospinal fluid (CSF) Gas6 is increased in AD patients compared to controls (63 versus 67 subjects; median value 13.3 versus 9.1 ng/ml; p < 0.0001). Thereafter, we assessed whether CSF Gas6 concentration was correlated to the following parameters: disease duration, MMSE score two years after clinical diagnosis, AD CSF biomarkers, and years of formal schooling. We detected an inverse correlation between CSF Gas6 levels at diagnosis and both disease duration (p < 0.0001) and decrease in the MMSE score two years later (p < 0.0001). Conversely, we found no correlation between CSF Gas6 and both AD biomarkers and years of formal schooling. In conclusion, our results suggest that upregulation of CSF Gas6 may be part of a defensive response aimed at counteracting AD progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-160599DOI Listing
February 2018